The present invention is generally related to transdermal drug delivery and more particularly to a reservoir-electrode for iontophoresis that has enhanced stability properties.
Iontophoretic delivery of a medicament is accomplished by application of a voltage to a medicament loaded reservoir-electrode, sufficient to maintain a current between the medicament loaded reservoir-electrode and a return electrode (another electrode) applied to a patient""s skin so that an ionic form of the desired medicament is delivered to the patient.
Shelf storage stability problems for many of the iontophoresis devices reported in the literature require that the medicament be stored separately from the reservoir-electrode until immediately prior to use. Iontophoretic delivery of medicaments is recognized as desirable for many medicaments, but it is not widely used because no devices are commercially available that meet all of the needs of the potential user population. An important requirement for a product to enjoy widespread usage is shelf storage stability. In an iontophoretic drug delivery system, one needs to be concerned not only with the drug stability, but also the stability of the delivery device and any interaction between the several components.
If a drug product is not stable under normal shelf storage conditions, it is unlikely to be a successfully commercial product because the short shelf life limits the products utility to most potential users as most of the product""s useful life is exhausted during the time required for manufacturing and the distribution process. Thus, determination of shelf storage stability is an important part of a drug product""s regulatory approval process. If there are difficulties with storage stability, regulatory approval may be withheld. Often, in iontophoretic devices the reservoir-electrode also is maintained in a dry (unhydrated) condition prior to use also because of the tendency of the active electrode material to undergo physical and chemical changes during shelf storage. Many drugs are not particularly stable to ambient conditions as the free base compound and as a result are formulated as salts that may react unfavorably with electrodes in iontophoretic devices. The need to store the several components separately has limited the use of iontophoretic devices, since in order to use the device, the reservoir-electrode needs to be charged with the medicament and hydrated either by a practitioner or user immediately prior to use.
Several United States Patents disclose devices that attempt to overcome the problem of shelf storage stability and facilitate the preparation of the device for use. U.S. Pat. No. 5,320,598 discloses a dry-state iontophoretic drug delivery device that has drug and electrolyte reservoirs that are initially in a non-hydrated condition. The device has a liquid containing pouch or breakable capsules that contain water or other liquid, the liquid being releasable by disrupting the liquid containers prior to use. Commercial manufacture of a device utilizing this disclosure would be complex.
U.S. Pat. No 5,385,543 also discloses a dry-state iontophoretic drug delivery device that has drug and electrolyte reservoirs. The disclosed device includes a backing layer with at least one passageway therethrough that allows the introduction of water or other liquids into the drug and electrolyte reservoirs prior to use followed by joining the reservoirs to the electrodes. The patent teaches that by joining the reservoirs to the electrodes after hydration, delamination problems are reduced.
No commercial products utilizing the technology disclosed either in the ""598 or the ""543 patents have been produced.
A different approach to the shelf storage stability problem is disclosed in U.S. Pat. No. 5,817,044. In this disclosure, the device is divided or otherwise separated into at least two portions, with one portion containing the electrode reservoir and the other containing the drug reservoir, which may include a medication in a dry form. In this disclosure, the user causes the two portions to come into electrical conducting contact with one another to at least partially hydrate one of the reservoirs, by either folding the device to bring the two portions into contact with one another or by removing a barrier dividing the two portions. While this device seems to be somewhat easier to use than the devices disclosed in the above patents, there currently is no commercial device that utilizes this disclosure.
International Application WO 98/208869 discloses an iontophoretic device for delivery of epinephrine and lidocaine HCl. The disclosed device includes materials that deter microbial growth and anti-oxidants to enhance the stability of epinephrine. While this disclosure recognizes the need for shelf storage stability and addresses the problem of epinephrine stability by including anti-oxidants, there is no recognition of the need to prevent corrosion of the electrodes during manufacture and shelf storage. Again, there is no commercial product based on the information in this disclosure.
A commercial iontophoretic device for delivery of lidocaine and epinephrine is provided under the tradename xe2x80x9cNumby Stuffxe2x80x9d by the Iomed Corp., Salt Lake City, Utah. The xe2x80x9cNumby Stuffxe2x80x9d device kit includes a vial sealed with a rubber septum containing a trademarked xe2x80x9cIontocainexe2x80x9d solution that includes Lidocaine HCl 2% and Epinephrine 1:100,000 that is used for charging the xe2x80x9cPhoresorxe2x80x9d system immediately prior to use. The xe2x80x9cNumby Stuffxe2x80x9d device lists U.S. Pat. Nos. 4,752,285; 5,374,241; 4,416,274; 5,135,477; and 5,415,628 that describe aspects of the device. None of these patents disclose a medicament-charged iontophoretic device with a useful shelf life. The patents are directed toward aspects of the delivery process and reservoir-electrode design. While these disclosures do potentially address the problem of keeping the medicament stable by isolating it from moisture, oxidation or from other components of the device, there is the problem, not previously recognized in the literature, corrosion of the active electrode during manufacture and storage. This problem is best understood by considering an electrochemical cell consisting of the silver/silver chloride electrode system commonly used in iontophoretic devices. In the cell considered, the Ag/AgCl electrode can be surround by solution of different chloride ion concentrations (Cl1 and Cl2. The electrode reaction is illustrated by
Ag+Clxe2x88x92=AgCl+exe2x88x92.
The Nernst equation describing this cell is
xcex94E0=RT/nF ln[Cl1]/[Cl2].
The Nernst equation illustrates that a chloride concentration gradient ([Cl1] not equal to [Cl2]) results in an open circuit potential, commonly called a concentration potential, that results in corrosion.
xcex94E0=open circuit potential as the concentration of Clxe2x88x92 moves away from unit concentration or activity.
Based on the Nernst equation""s dependency on the log of the chloride ion concentration, the effect on the open circuit potential is about 60 millivolts (mV) per decade (101) in concentration of chloride ion. Silver/silver chloride electrodes are the most common iontophoretic electrodes, and these electrodes require chloride ion to function. Most iontophoretic medicaments are provided as the hydrochloride salt and are added to the reservoir at some point prior to use. The practical effect of this phenomenon is, since the log of zero is infinity, that when chloride ion is added to the device before use, before the concentration of chloride ion can fully equilibrate, there is likely already some corrosive damage to the patch due to concentration differentials. Thus, there is often some corrosive damage to the reservoir-electrode interface almost immediately upon the addition of chloride ion containing constituents to the reservoir. Additionally, if the chloride ion addition is non-uniform, some corrosive conversion of silver to silver chloride is almost guaranteed to occur. Several problems can arise from this corrosion to the electrode including: a loss of pharmaceutical elegance; a cut-off of the operation of the reservoir-electrode because of an open circuit; localized pH changes in the reservoir-electrode during operation; a reduction in the amount of silver available to the desired electrochemical reaction during iontophoresis; and actual delivery of silver ion to the patient resulting in a xe2x80x9ctattooxe2x80x9d. One way to deal with this chloride concentration gradient problem is to use sufficient excess amounts of silver so that the reservoir-electrode is still substantially functional despite some corrosion. Often, even if excess silver is used, localized corrosion can produce in a break in the electrode continuity at a junction point and result in, at least, a partially non-functional reservoir-electrode. A further safety related problem may occur if a portion of the reservoir electrode is non-functional. When a portion of the reservoir electrode is non-functional, the full current of the controller is applied to a smaller area of the reservoir-electrode resulting in an undesirably high current density. The higher current density may cause undesirable effects to the patient ranging from a xe2x80x9ctinglingxe2x80x9d sensation from the increased current to damage to the skin contact area. Additionally, since silver is a xe2x80x9cpreciousxe2x80x9d metal, the use of excess silver also adversely effects the cost, and ultimately, the possible commercialization of iontophoretic drug delivery.
Another way to minimize the effect of the rapid onset of corrosion due to a chloride ion concentration gradient is to form the reservoir electrode from a very absorbent material, so that the hydration process occurs rapidly, minimizing the duration of any concentration gradient. While a very absorbent reservoir reduces the problem of corrosion when loading, such an absorbent material generally readily expresses liquid upon compression and, additionally, does not have any self-adhesive properties that helps the adherence of the reservoir material to the electrode or to the patient""s skin.
Most commonly, an iontophoretic reservoir is formed from a hydrogel. Hydrogels are absorbent and generally do not express liquid upon compression, but a medicament may be slow to absorb into the hydrogel, and as a result, the slow rate of absorption amplifies the problem of concentration gradient induced corrosion before equilibrium concentration is achieved. Currently, the only way a hydrogel reservoir may be incorporated into an iontophoretic reservoir-electrode is to charge the hydrogel reservoir with the desired aliquot of medicament independently of the electrode, allow the medicament solution to equilibrate within the hydrogel, a process which can easily require several days and then laminate the loaded hydrogel to the electrode to form the reservoir-electrode. The separate hydrogel loading process is not amenable to continuous high-speed manufacturing and adversely effects the potential for commercialization of hydrogel based reservoir-electrodes.
If a reservoir-electrode were available that addressed the problem of corrosion between the electron conductor and the ion conductor interface due to electrolyte concentration imbalances so that the device could be preloaded with medicament and still have acceptable shelf storage stability, the practicability of iontophoretic drug delivery would be enhanced. If such a reservoir-electrode also had sufficient adhesive properties to enhance adherence of the reservoir material to the electrode and to the patient""s skin, the art of iontophoresis would be further enhanced. Such a reservoir-electrode is disclosed hereinbelow.
A reservoir-electrode for an iontophoretic delivery device of the present invention includes an electrode having a surface; and a hydrophilic reservoir situated in electrically conductive relation to the electrode. The reservoir is formed from an absorbent material having a substantially uniform concentration of an alkali metal salt therein thereby substantially eliminating concentration gradients of the salt with respect to the electrode surface so that when an aliquot of a medicament solution including ions of the salt is added to the reservoir substantially no corrosion potential develops at the surface of the electrode, thereby substantially eliminating a corrosive effect on the electrode.
An iontophoretic system of the present invention includes a first-reservoir electrode including at least one medicament for delivery to a patient. The first reservoir-electrode includes a first hydrophilic reservoir situated in electrically conductive relation to a first electrode with a surface. The first reservoir is formed from a bibulous hydrophilic cross-linked polymeric material having a substantially uniform concentration of an alkali metal chloride salt therein thereby substantially eliminating concentration gradients of the salt with respect to the electrode surface when an aliquot of at least one medicament including ions of the alkali metal chloride salt is added to the reservoir electrode. The polymeric material has a first surface and a second surface that is adhesively adherent to the electrode. The first surface of the polymeric material is releasably adhesive to an applied area of a patient""s skin. The polymeric material has a cohesive strength, wherein a bond strength of an adhesive bond between the second surface of said polymeric material to the first electrode is greater than the cohesive strength of said polymeric material and an adhesive bond strength of the first surface of the polymeric material to the applied area of the patient is less than the cohesive strength of said polymeric material so that upon removal of the first reservoir-electrode from the applied area of the patient, substantially no polymeric material remains on the applied the said first electrode.
The iontophoretic system of the invention also includes a second reservoir-electrode including a second hydrophilic reservoir situated in electrically conductive relation to a second electrode with a surface. The second reservoir is formed from a bibulous hydrophilic cross-linked polymeric material having a substantially uniform concentration of an alkali metal chloride salt therein thereby substantially eliminating concentration gradients of the salt with respect to the second electrode. The polymeric material has a first surface and a second surface is adhesively adherent to the second electrode. The first surface of the polymeric material is releasably adhesive to an applied area of a patient""s skin. The polymeric material has a cohesive strength, wherein a bond strength of an adhesive bond between the second surface of the polymeric material to the second electrode is greater than the cohesive strength of said polymeric material and an adhesive bond strength of the first surface of the polymeric material to the applied area of the patient is less than the cohesive strength of the polymeric material so that upon removal of the second reservoir-electrode from the applied area of the patient, substantially no polymeric material remains on the applied area and the second reservoir remains substantially intact and adhesively adherent to said second electrode. The iontophoretic system of the invention further includes a power supply disposed in electrically conductive contact with the first reservoir-electrode and the second reservoir-electrode to supply a preselected current so that when the first reservoir-electrode and the second reservoir-electrode are each applied to a patient, a complete electrical circuit is formed with the first reservoir-electrode operating as an anode and the second reservoir-electrode operating as a cathode, thereby delivering the at least one medicament to the patient.
The reservoir-electrode of the invention and the iontophoretic device incorporating reservoir-electrodes of the invention as both the active and the return reservoir-electrodes have demonstrated satisfactory shelf storage stability. The reservoir-electrode of the invention can be efficiently produced and, with the satisfactory shelf storage stability provided by overcoming the problem of electrode corrosion during storage, provides the opportunity for a previously unavailable commercial iontophoretic device that answers the both the needs of patients and commercial distribution requirements.